Preparation of microparticles having improved flowability

ABSTRACT

Methods for preparing microparticles having improved flowability to facilitate processing in automated equipment. Microparticles are maintained at a conditioning temperature for a period of time. The conditioning temperature and period are selected so that the angle of repose of the microparticles is less than about 28°.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to preparation of microparticlescontaining an active agent. More particularly, the present inventionrelates to microparticles having improved flowability, and to a methodfor the preparation of such microparticles.

[0003] 2. Related Art

[0004] Various methods are known by which compounds can be encapsulatedin the form of microparticles. It is particularly advantageous toencapsulate a biologically active or pharmaceutically active agentwithin a biocompatible, biodegradable wall-forming material (e.g., apolymer) to provide sustained or delayed release of drugs or otheractive agents. In these methods, the material to be encapsulated (drugsor other active agents) is generally dissolved, dispersed, or emulsifiedin a solvent containing the wall forming material. Solvent is thenremoved from the microparticles to form the finished microparticleproduct.

[0005] An example of a conventional microencapsulation process isdisclosed in U.S. Pat. No. 3,737,337 wherein a solution of a wall orshell forming polymeric material in a solvent is prepared. The solventis only partially miscible in water. A solid or core material isdissolved or dispersed in the polymer-containing solution and,thereafter, the core-material-polymer-containing solution is dispersedin an aqueous liquid that is immiscible in the organic solvent in orderto remove solvent from the microparticles.

[0006] Tice et al. in U.S. Pat. No. 4,389,330 describe the preparationof microparticles containing an active agent by using a two-step solventremoval process. In the Tice et al. process, the active agent and thepolymer are dissolved in a solvent. The mixture of ingredients in thesolvent is then emulsified in a continuous-phase processing medium thatis immiscible with the solvent. A dispersion of microparticlescontaining the indicated ingredients is formed in the continuous-phasemedium by mechanical agitation of the mixed materials. From thisdispersion, the organic solvent can be partially removed in the firststep of the solvent removal process. After the first stage, thedispersed microparticles are isolated from the continuous-phaseprocessing medium by any convenient means of separation. Following theisolation, the remainder of the solvent in the microparticles is removedby extraction. After the remainder of the solvent has been removed fromthe microparticles, they are dried by exposure to air or by otherconventional drying techniques.

[0007] Another conventional method of microencapsulating an agent toform a microencapsulated product is disclosed in U.S. Pat. No.5,407,609. This method includes: (1) dissolving or otherwise dispersingone or more agents (liquids or solids) in a solvent containing one ormore dissolved wall-forming materials or excipients (usually thewall-forming material or excipient is a polymer dissolved in a polymersolvent); (2) dispersing the agent/polymer-solvent mixture (thediscontinuous phase) into a processing medium (the continuous phasewhich is preferably saturated with polymer solvent) to form an emulsion;and (3) transferring all of the emulsion immediately to a large volumeof processing medium or other suitable extraction medium, to immediatelyextract the solvent from the microdroplets in the emulsion to form amicroencapsulated product, such as microcapsules or microspheres.

[0008] U.S. Pat. No. 5,650,173 discloses a process for preparingbiodegradable, biocompatible microparticles comprising a biodegradable,biocompatible polymeric binder and a biologically active agent, whereina blend of at least two substantially non-toxic solvents, free ofhalogenated hydrocarbons, are used to dissolve both the agent and thepolymer. The solvent blend containing the dissolved agent and polymer isdispersed in an aqueous solution to form droplets. The resultingemulsion is added to an aqueous extraction medium preferably containingat least one of the solvents of the blend, whereby the rate ofextraction of each solvent is controlled, whereupon the biodegradable,biocompatible microparticles containing the biologically active agentare formed. Active agents suitable for encapsulation by this processinclude, but are not limited to, norethindrone, risperidone, andtestosterone, and a preferred solvent blend is one comprising benzylalcohol and ethyl acetate.

[0009] U.S. Pat. No. 5,654,008 describes a microencapsulation processthat uses a static mixer. A first phase, comprising an active agent anda polymer, and a second phase are pumped through a static mixer into aquench liquid to form microparticles containing the active agent.

[0010] The documents described above all disclose methods that can beused to prepare microparticles that contain an active agent. However,flowability of these microparticles immediately after processing andrecovery may be poor. Good flowability is characterized by steady,controlled flow similar to dry sand. Poor flowability, on the otherhand, is characterized by uncontrolled, erratic flow similar to wetsand. In this case the entire bulk tries to move in a solid mass. Thislast condition is termed “floodable” flow and is most characteristic ofcohesive, sticky powders. Flowability is an important consideration inlarge-scale processing when invariably these powders or microparticlesmust be moved from place to place. It is a particularly importantconsideration when using automated filling equipment where material mustflow from a hopper. Microparticles having poor flow properties tend to“arch” or “bridge” and then may “rat hole” or stop completely whendischarged from the hopper. In this case further processing must beabandoned. None of the documents discussed above discloses a specificmethod for preparing microparticles that have improved flowability.

[0011] Thus, there is a need in the art for a method for preparingmicroparticles having improved flowability. There is a further need inthe art for a method for preparing microparticles with improvedflowability so that such microparticles can be processed in automatedpowder filling equipment. The present invention, the description ofwhich is fully set forth below, solves the need in the art for suchmethods.

SUMMARY OF THE INVENTION

[0012] The present invention relates to a method for preparingmicroparticles that have improved flowability. In one aspect, a methodfor processing a quantity of microparticles is provided. The methodcomprises placing, the quantity of microparticles into a container, andmaintaining the microparticles at a conditioning temperature for aperiod of time. The conditioning temperature and the period are selectedso that an angle of repose of the quantity of microparticles is lessthan about 28°.

[0013] In another aspect of the present invention, a method forpreparing microparticles having improved flowability is provided. Themethod comprises: preparing an emulsion that comprises a first phase anda second phase, the first phase comprising an active agent, a polymer,and a solvent for the polymer; extracting the solvent from the emulsionto form microparticles containing the active agent; and maintaining themicroparticles at a conditioning temperature for a period of time, theconditioning temperature and the period being selected so that an angleof repose of the microparticles is less than about 28°.

[0014] In yet another aspect of the present invention, microparticleshaving improved flowability are provided. Such microparticles may beprepared by any of the methods described and disclosed herein, includinga method comprising: preparing an emulsion that comprises a first phaseand a second phase, the first phase comprising an active agent, apolymer, and a solvent for the polymer; extracting the solvent from theemulsion to form microparticles containing the active agent; andallowing crystal growth of active agent present on a surface of themicroparticles. In a preferred aspect of the present invention, thecrystal growth of active agent on the surface of the microparticlestakes place while the microparticles are maintained at a conditioningtemperature for a period of time, the conditioning temperature and theperiod being selected so that an angle of repose of the microparticlesis less than about 28°.

[0015] Features and Advantages

[0016] A feature of the present invention is that it providesmicroparticles having improved flowability. More particularly, thepresent invention advantageously provides microparticles havingsignificantly improved flowability to facilitate processing in certainautomated equipment, such as certain automated vial filling machines andtabletting machines.

[0017] Another feature of the method of the present invention is that itproduces microparticles in stable form that should remain unchangedduring normal storage conditions. Advantageously, the present inventionspecifically provides for crystal growth of active agent on the surfaceof the microparticles.

[0018] An advantage of the present invention is that the process call becarried out in readily available, completely closed containerseliminating the need for further processing or product transfers,thereby preserving the sterility of the microparticles. In this manner,there is no need for further sterilization.

[0019] Another advantage of the present invention is that the processcan be carried out at a temperature much lower than the glass transitiontemperature T_(g) of the polymer. Processing at such a temperatureadvantageously minimizes the product agglomeration and instability thattypically occurs at temperatures nearer to or above the polymer T_(g).

[0020] Poor flowability often results from conventional formulation andprocessing techniques for microparticles. By solving the poorflowability problem as a final processing step, the present inventionadvantageously avoids reformulation or redesign of establishedformulations, processes, and equipment.

BRIEF DESCRIPTION OF THE FIGURES

[0021] The present invention is described with reference to theaccompanying drawings. In the drawings, like reference numbers indicateidentical or functionally similar elements. Additionally, the left-mostdigit of a reference number identifies the drawing in which thereference number first appears.

[0022]FIG. 1 depicts measurement of angle of repose for microparticles;

[0023]FIGS. 2A and 2B show micrographs of microparticles prior tocarrying out one embodiment of a process of the present invention; and

[0024]FIGS. 3A and 3B show micrographs of microparticles after carryingout one embodiment of a process of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Overview

[0026] The present invention relates to microparticles having improvedflowability, and to methods for the preparation of such microparticles.“Flowability” refers to the ability of microparticles to flow.Microparticles exhibiting poor flowability stick to one another, and“bridge” together such as when they are processed through certainautomated filling equipment and hoppers. Conversely, microparticlesexhibiting good flowability flow freely, and can be processed inautomated filling or tabletting equipment without significant occurrenceof bridging or hold-up.

[0027] The angle of repose of the microparticles can be used tocharacterize the flowability of the microparticles. As known to oneskilled in the art, “angle of repose” refers to the limiting angle ofincline, θ_(r), at which a body on the incline will remain at rest. Forthe body at rest on the incline, the frictional force f may have anyvalue up to a maximum μ_(s)N, where μ_(s) is the coefficient of staticfriction and N is the normal force. The angle of repose, θ_(r), isrelated to μ_(s) by the equation:

tan θ_(r)=μ_(s)

[0028] Particularly, as will be described in more detail below,microparticles processed in accordance with the methods of the presentinvention flowed freely and demonstrated angles of repose less thanabout 28°. In contrast, microparticles not subject to the conditioningprocess of the present invention bridged in filling hoppers anddemonstrated angles of repose greater than about 35°.

[0029] In one embodiment of the present invention, a conditioningprocess is carried out on the microparticles. The conditioning processis carried out on a finished microparticle product, prior to any fillingoperation. It should be readily apparent to one skilled in the art, thatthe present invention is not limited to any particular method ofpreparing a finished microparticle product. For example, finishedmicroparticles can be prepared using emulsion-based methods of preparingmicroparticles. Alternatively, phase separation methods can be used toprepare finished microparticles. Suitable methods of preparing afinished microparticle product are disclosed in, for example, thefollowing U.S. patents, the entirety of each of which is incorporatedherein by reference: U.S. Pat. Nos. 3,737,337; 4,389,330; 5,407,609;5,650,173; 5,654,008; 5,792,477; 5,916,598; and 6,110,503.

[0030] In one aspect, the method of the present invention comprisesplacing a batch or other quantity of microparticles into a closedcontainer. The closed container is maintained at a conditioningtemperature for a period of time. The conditioning temperature and theperiod are selected so that an angle of repose of the batch ofmicroparticles is less than about 28°. Preferably, the closed containeris rotated or inverted during the period to provide mixing, therebyreducing or eliminating any temperature gradient that may be present.After the period, the batch of microparticles can be transferred to avial filling machine to fill vials with the microparticles, or to atabletting machine or the like for further processing.

[0031] In one preferred embodiment of the present invention, themicroparticles are made using an emulsion-based process. In such apreferred embodiment, the method of the present invention includespreparing an emulsion that comprises a first phase and a second phase.The first phase preferably comprises an active agent, a polymer, and asolvent for the polymer. The second phase is a continuous phase,preferably an aqueous phase. The solvent is extracted from the emulsionto firm microparticles containing the active agent. The microparticlesare maintained at a conditioning temperature for a period of time. Theconditioning temperature and the period are selected so that an angle ofrepose of the microparticles is less than about 28°.

[0032] To ensure clarity of the description that follows, the followingdefinitions are provided. By “microparticles” or “microspheres” is meantsolid particles that contain an active agent or other substancedispersed or dissolved within a polymer that serves as a matrix orbinder of the particle. The polymer is preferably biodegradable andbiocompatible. By “biodegradable” is meant a material that shoulddegrade by bodily processes to products readily disposable by the bodyand should not accumulate in the body. The products of thebiodegradation should also be biocompatible with the body. By“biocompatible” is meant not toxic to the body, is pharmaceuticallyacceptable, is not carcinogenic, and does not significantly induceinflammation in body tissues. As used herein, “body” preferably refersto the human body, but it should be understood that body can also referto a non-human animal body. By “weight %” or “% by weight” is meantparts by weight per hundred parts total weight of microparticle. Forexample, 10 wt. % active agent would mean 10 parts active agent byweight and 90 parts polymer by weight. Unless otherwise indicated to thecontrary, percentages (%) reported herein are by weight. By “controlledrelease microparticle” or “sustained release microparticle” is meant amicroparticle from which an active agent or other type of substance isreleased as a function of time. By “mass median diameter” is meant thediameter at which half of the distribution (volume percent) has a largerdiameter and half has a smaller diameter.

[0033] Methods of the Present Invention

[0034] The present invention provides a method to improve flowability ofa microparticle product, preferably a microparticle comprised of anactive agent and a biodegradable polymer. The flowability of themicroparticle product is improved to allow processing in conventionalhoppers and automated vial filling equipment. Without the method of thepresent invention, poor microparticle flow characteristics result inbridging in powder hoppers and subsequent inability to process themicroparticle product in automated equipment.

[0035] In accordance with the present invention, a conditioning processis carried out on a finished microparticle product, such as a batch orquantity of microparticles prepared by the process disclosed anddescribed in U.S. Pat. Nos. 5,654,008 and 5,650,173. The batch ofmicroparticles is maintained at a conditioning temperature for a periodof time. The conditioning temperature and the period are selected sothat an angle of repose of the batch of microparticles is less thanabout 28°. This conditioning process is preferably carried out at atemperature below the T_(g) of the polymer to avoid productagglomeration. To promote crystal growth of the active agent on thesurface of the microparticle (described in detail below), theconditioning process is preferably carried out in an open container sothat the microparticles may be exposed to elevated humidity or moisturevapor. However, use of an open container and exposure of themicroparticles to moisture vapor may compromise the sterility andstability of the final product. Therefore, to ensure sterility andstability of the microparticles, the conditioning process is carried outin a closed container with a dry product. For example, the conditioningprocess may be carried out in a completely closed container, which isplaced in a controlled-temperature chamber. The temperature in thechamber, and the length of time the container is in the chamber, areboth controlled. Preferably, the container is rotated or inverted whileit is in the chamber to provide mixing. Processing the material in aclosed container preserves the sterility of the microparticle product,avoids yield losses and contamination associated with handling andproduct transfers, and minimizes moisture pick-up by avoidingatmospheric contact.

[0036] Batches of microparticles containing risperidone were prepared atthe twenty-kilogram scale using the following process. The 20 Kg process(8 kg of active agent and 12 kg of polymer) provides a theoretical drugloading of the microparticles of 40% (8 kg/20 kg×100%).

[0037] A 16.7 wt. % polymer solution was prepared by dissolving 12 kg ofMEDISORB® 7525 DL polymer (Alkermes, Inc., Blue Ash, Ohio) in ethylacetate. A 24 wt. % drug solution was prepared by dissolving 8 kg ofrisperidone (Janssen Pharmaceutica, Beerse, Belgium) in benzyl alcohol.An active agent/polymer solution (organic phase) was prepared by mixingthe drug solution into the polymer solution. The active agent/polymersolution was maintained at a temperature of 25±5° C.

[0038] The second, continuous phase was prepared by preparing a 600liter solution of 1% PVA, the PVA acting as an emulsifier. To this wasadded 42 kg of ethyl acetate to form a 6.5 wt. % solution of ethylacetate. The two phases were combined using a static mixer such as a 1″Kenics static mixer available from Chemineer, Inc., North Andover, Mass.

[0039] The emulsion was transferred to a solvent extraction medium. Thesolvent extraction medium was 2.5% solution of ethyl acetate andwater-for-injection (WFI) at 5-10° C. The volume of the solventextraction medium is 0.25 L per gram of batch size.

[0040] After completion of the solvent extraction step, themicroparticles were collected, de-watered, and dried. The temperaturewas maintained at less than about 15° C.

[0041] The microparticles were then re-slurried in a re-slurry tankusing a 25% ethanol solution. The temperature in the re-slurry tank wasin the range of about 0° C. to about 15° C. The microparticles were thentransferred back to the solvent extraction tank for washing with anotherextraction medium (25% ethanol solution) that was maintained atpreferably 25°±1° C.

[0042] The microparticles were collected, de-watered, and dried. Thetemperature was warmed to greater than about 20° C. but below 40° C.

[0043] As will be demonstrated below, the conditioning process of thepresent invention, wherein the microparticles are maintained at aconditioning temperature for a period of time, improves the flowabilityof microparticles. Table 1 below shows the effect of the conditioningprocess on angle of repose for samples of risperidone microparticlesprepared in the manner described above.

[0044] The angle of repose was measured in the following manner. Astandard 100 mm Nalgene funnel was positioned in a ring stand so thatthe funnel discharge was at a height of approximately three inches abovea level horizontal surface. Approximately 100 g of microparticles wereweighed out. The microparticles were placed in the funnel, which wasfitted with a stopper to block discharge. The stopper was removed, andthe microparticles were allowed to flow through the funnel until allmaterial was discharged. The discharged microparticles formed a pilehaving an angle of repose characteristic of the microparticles formingthe pile. A pile 100 of microparticles is depicted in FIG. 1. The heightof the pile (h), the diameter of the pile (d), and the width (w) wherethe height of the pile was measured, were all recorded. The angle ofrepose was calculated from the recorded dimensions in accordance withthe following formula:$\theta_{r} = {\tan^{- 1}\left( \frac{{height}(h)}{{width}(w)} \right)}$

[0045] θ_(r) is the angle of incline at which the microparticles formingpile 100 remain at rest. Microparticles that are poor flowing have ahigher angle of repose (i.e., form a taller pile with greater height(h)) than microparticles that have greater flowability. Conversely,microparticles with improved flowability have a lower angle of repose(i.e., form a shorter and wider pile with lower height (h)) thanmicroparticles having poorer flowability.

[0046] Although the diameter of the pile (d) was not needed to calculateθ_(r), the parameter (d) provided additional qualitative informationabout flowability. As can be seen from FIG. 1, if (d) is not equal totwice the width (w), then a truncated cone (pointed top of cone istruncated) has been formed. It was observed that microparticles havinggood flowability tended to form a truncated cone, while microparticleshaving poorer flowability tended to form a more defined cone with (d)substantially equal to twice the width (w). TABLE 1 Angle of Flow SampleTreatment Repose (°) Property (unsifted) None 38.7 Poor (sifted)¹ None37.5 Poor 36.9 (unsifted) 24 hours @ 72° F. 25.6 Good 27.6 (sifted)¹ 1week @ 72° F. 21.3 Excellent 23.7

[0047] Table 1 shows for each sample the treatment, or conditioningprocess, to which the sample of microparticles was subjected, the angleof repose, and an assessment of the flowability or flow property. Thefirst two samples exhibiting poor flowability were not subjected to theconditioning process of the present invention. The angle of repose forthese microparticles was greater than 35°. The sample exhibiting goodflowability was maintained at a conditioning temperature of 72° F. for aperiod of 24 hours; the angle of repose for these microparticles wasbetween about 25.6° and 27.6°. The flowability of the microparticlesimproved to excellent by maintaining the microparticles for one week at72° F., as shown by the last sample in Table 1. The angle of repose forthe last sample in Table 1 was between about 21.3° and 23.7°.

[0048] Another batch of risperidone microparticles was prepared in themanner described above. The effect of conditioning time on angle ofrepose for this batch of microparticles is shown below in Table 2. TABLE2 Days at Angle of Flow 20-25° C. Repose (°) Property 0 41.9 Poor 2 24.8Good 3 23.2 Good 4 23.2 Good 5 21.8 Excellent 6 18.4 Excellent

[0049] Table 2 shows the angle of repose and flow property as a functionof the number of days the microparticles are maintained at aconditioning temperature in the range of 20-25° C. At zero () days,corresponding to no conditioning process, the flowability of themicroparticles was poor, and the angle of repose was about 42°. As thelength of the conditioning period (days at 20-25° C.) increased, theflowability of the microparticles improved. The improved flowability ischaracterized by a decrease in the angle of repose. Acceptableflowability for processing of the microparticles in automated fillingequipment is characterized by an angle of repose in the range of fromabout 18° to about 28°. However, it should be understood that thepresent invention is not limited to angles in this range. It ispreferred to have the angle of repose as low as possible below about28°.

[0050] In order to more fully characterize the micrographs exhibitingimproved flowability, atomic force microscopy (AFM) micrographs wereprepared for microparticles prior to the conditioning process of thepresent invention, and for the same microparticles after carrying outthe conditioning process of the present invention. In AFM, a stylus,having a tip diameter on the order of 10-20 nm and a length of about10μ, scans across the surface of a sample while oscillating verticallyor “tapping.” Deflection data of the stylus provides both geometric andcompositional information about the surface of the sample.

[0051] AFM micrographs were prepared for samples of microparticles fromthe batches reported in Table 1 and another batch of risperidonemicroparticles prepared in the manner described above. One set ofmicrographs was prepared on “pre-conditioned” microparticles, i.e.,prior to carrying out the conditioning process of the present invention.The pre-conditioned micrographs are presented in FIGS. 2A and 2B. Themicrographs of FIGS. 2A and 2B exhibit large dark-phase patches 200 ofwhat appear to be nanocrystalline or amorphous material.

[0052] Another set of micrographs was prepared on “post-conditioned”microparticles, i.e., after carrying out the conditioning process of thepresent invention. The post-conditioned micrographs are presented inFIGS. 3A and 3B. The micrographs of FIGS. 3A and 3B exhibit larger (upto several microns in length) and much more numerous crystals 300 thanwere present on the pre-conditioned micrographs of FIGS. 2A and 2B.

[0053] As evidenced by the pre-conditioned micrographs of FIGS. 2A and2B, the microparticles included active agent (in this case risperidone)on the surface largely in amorphous form. As evidenced by thepost-conditioned micrographs of FIGS. 3A and 3B, through theconditioning process of the present invention, the active agent on thesurface of the microparticles is converted to largely crystalline form.The post-conditioned microparticles with the surface active agent incrystalline form exhibited improved flowability as discussed above.Thus, by allowing crystal growth of the active agent present on asurface of the microparticles, microparticles having improvedflowability can be prepared in accordance with the present invention.

[0054] As evidenced by FIGS. 2A-3B, the crystal growth of risperidone onthe surface of the microparticles occurred during the conditioningprocess of the present invention. The conditioning process was carriedout at a conditioning temperature in the range of from about 20° C. toabout 25° C. These temperatures are also much less than the polymerT_(g) (approximately 45° C.), which is preferred since it avoids thepossibility of product agglomeration.

[0055] Preferred active agents that can be encapsulated by the processof the present invention include 1,2-benzazoles, more particularly,3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles.The most preferred active agents of this kind for treatment by theprocess of the present invention are3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(“risperidone”) and3-[2-[4-(6-fluro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(“9-hydroxyrisperidone”) and the pharmaceutically acceptable saltsthereof. Risperidone (which term, as used herein, is intended to includeits pharmaceutically acceptable salts) is most preferred. Risperidonecan be prepared in accordance with the teachings of U.S. Pat. No.4,804,663, the entirety of which is incorporated herein by reference.9-hydroxyrisperidone can be prepared in accordance with the teachings ofU.S. Pat. No. 5,158,952, the entirety of which is incorporated herein byreference.

[0056] Preferred examples of polymer matrix materials includepoly(glycolic acid), poly(d,1-lactic acid), poly(1-lactic acid),copolymers of the foregoing, and the like. Various commerciallyavailable poly(lactide-co-glycolide) materials (PLGA) may be used in themethod of the present invention. For example, poly(d,1-lactic-co-glycolic acid) is commercially available from Alkermes,Inc. (Blue Ash,, Ohio). A suitable product commercially available fromAlkermes, Inc. is a 50:50 poly(d,1-lactic-co-glycolic acid) known asMEDISORB® 5050 DL. This product has a mole percent composition of 50%lactide and 50% glycolide. Other suitable commercially availableproducts are MEDISORB® 6535 DL, 7525 DL, 8515 DL and poly(d,1-lacticacid) (100 DL). Poly(lactide-co-glycolides) are also commerciallyavailable from Boehringer Ingelheim (Germany) under its Resomer® mark,e.g., PLGA 50:50 (Resomer® RG 502), PLGA 75:25 (Resomer® RG 752) andd,1-PILA (Resomer® RG 206), and from Birmingham Polymers (Birmingham,Ala.). These copolymers are available in a wide range of molecularweights and ratios of lactic acid to glycolic acid.

[0057] The most preferred polymer for use in the practice of theinvention is the copolymer, poly(d,1-lactide-co-glycolide). It ispreferred that the molar ratio of lactide to glycolide in such acopolymer be in the range of from about 85:15 to about 50:50.

[0058] The molecular weight of the polymeric matrix material is of someimportance. The molecular weight should be high enough to permit theformation of satisfactory polymer coatings, i.e., the polymer should bea good film former. Usually, a satisfactory molecular weight is in therange of 5,000 to 500,000 daltons, preferably about 150,000 daltons.However, since the properties of the film are also partially dependenton the particular polymeric matrix material being used, it is verydifficult to specify an appropriate molecular weight range for allpolymers. The molecular weight of the polymer is also important from thepoint of view of its influence upon the biodegradation rate of thepolymer. For a diffusional mechanism of drug release, the polymer shouldremain intact until all of the drug is released from the microparticlesand then degrade. The drug can also be released from the microparticlesas the polymeric excipient bioerodes. By an appropriate selection ofpolymeric materials a microparticle formulation can be made in which theresulting microparticles exhibit both diffusional release andbiodegradation release properties. This is useful in accordingmultiphasic release patterns.

[0059] The formulation prepared by the process of the present inventioncontains an active agent dispersed in the microparticle polymeric matrixmaterial. The amount of such agent incorporated in the microparticlesusually ranges from about 1 wt. % to about 90 wt. %, preferably 30 to 50wt. %, more preferably 35 to 40 wt. %.

[0060] Other biologically active agents include non-steroidalantifertility agents; parasympathomimetic agents; psychotherapeuticagents; tranquilizers; decongestants; sedative hypnotics; steroids;sulfonamides; sympathomimetic agents; vaccines; vitamins; antimalarials;anti-migraine agents; anti-Parkinson agents such as L-dopa;anti-spasmodics; anticholinergic agents (e.g. oxybutynin); antitussives;bronchodilators; cardiovascular agents such as coronary vasodilators andnitroglycerin; alkaloids; analgesics; narcotics such as codeine,dihydrocodienone, meperidine, morphine and the like; non-narcotics suchas salicylates, aspirin, acetaminophen, d-propoxyphene and the like;opioid receptor antagonists, such as naltrexone and naloxone;antibiotics such as gentamycin, tetracycline and penicillins;anti-cancer agents; anti-convulsants; anti-emetics; antihistamines;anti-inflammatory agents such as hormonal agents, hydrocortisone,prednisolone, prednisone, non-hormonal agents, allopurinol,indomethacin, phenylbutazone and the like; prostaglandins and cytotoxicdrugs.

[0061] Still other suitable active agents include estrogens,antibacterials; antifungals; antivirals; anticoagulants;anticonvulsants; antidepressants; antihistamines; and immunologicalagents.

[0062] Other examples of suitable biologically active agents includepeptides and proteins, analogs, muteins, and active fragments thereof,such as immunoglobulins, antibodies, cytokines (e.g. lymphokines,monokines, chemokines), blood clotting factors, hemopoietic factors,interleukins (IL-2, IL-3, IL-4, IL-6), interferons (β-IFN, α-IFN andγ-IFN), erythropoietin, nucleases, tumor necrosis factor, colonystimulating factors (e.g., GCSF, GM-CSF, MCSF), insulin, enzymes (e.g.,superoxide dismutase, tissue plasminogen activator), tumor suppressors,blood proteins, hormones and hormone analogs (e.g., growth hormone,adrenocorticotropic hormone and luteinizing hormone releasing hormone(LHRH)), vaccines (e.g., tumoral, bacterial and viral antigens);somatostatin; antigens; blood coagulation factors; growth factors (e.g.,nerve growth factor, insulin-like growth factor); protein inhibitors,protein antagonists, and protein agonists; nucleic acids, such asantisense molecules; oligonucleotides; and ribozymes. Small molecularweight agents suitable for use in the invention include, antitumoragents such as bleomycin hydrochloride, carboplatin, methotrexate andadriamycin; antipyretic and analgesic agents; antitussives andexpectorants such as ephedrine hydrochloride, methylephedrinehydrochloride, noscapine hydrochloride and codeine phosphate; sedativessuch as chlorpromazine hydrochloride, prochlorperazine hydrochloride andatropine sulfate; muscle relaxants such as tubocurarine chloride;antiepileptics such as sodium phenytoin and ethosuximide; antiulceragents such as metoclopramide; antidepressants such as clomipramine;antiallergic agents such as diphenhydramine; cardiotonics such astheophillol; antiarrhythmic agents such as propranolol hydrochloride;vasodilators such as diltiazem hydrochloride and bamethan sulfate;hypotensive diuretics such as pentolinium and ecarazine hydrochloride;antidiuretic agents such as metformin; anticoagulants such as sodiumcitrate and heparin; hemostatic agents such as thrombin, menadionesodium bisulfite and acetomenaphthone; antituberculous agents such asisoniazide and ethanbutol; hormones such as prednisolone sodiumphosphate and methimazole.

[0063] Conclusion

[0064] While various embodiments of the present invention have beendescribed above, it should be understood that they have been presentedby way of example only, and not limitation. The present invention is notlimited to a particular active agent, polymer or solvent, nor is thepresent invention limited to a particular scale or batch size. Thus, thebreadth and scope of the present invention should not be limited by anyof the above-described exemplary embodiments, but should be defined onlyin accordance with the following claims and their equivalents.

What is claimed is:
 1. A method for processing a quantity ofmicroparticles, comprising: (a) placing the quantity of microparticlesinto a container; (b) maintaining the microparticles at a conditioningtemperature for a period of time, wherein the conditioning temperatureand the period are selected so that an angle of repose of the quantityof microparticles is less than about 28°.
 2. The method of claim 1,further comprising after step (b): (c) transferring at least a portionof the quantity of microparticles into a vial filling machine.
 3. Themethod of claim 1, wherein the conditioning temperature is from about20° C. to about 25° C.
 4. The method of claim 3, wherein the period isat least two days.
 5. The method of claim 3, wherein the period is atleast five days.
 6. The method of claim 1, wherein step (b) comprises:(i) rotating the container.
 7. A method for preparing microparticleshaving improved flowability, comprising: (a) preparing an emulsion thatcomprises a first phase and a second phase, wherein the first phasecomprises an active agent, a polymer, and a solvent for the polymer; (b)extracting the solvent from the emulsion to form microparticlescontaining the active agent; (c) maintaining the microparticles at aconditioning temperature for a period of time, wherein the conditioningtemperature and the period are selected so that an angle of repose ofthe microparticles is less than about 28°.
 8. The method of claim 7,wherein step (b) comprises: (i) transferring the emulsion to a solventextraction medium.
 9. The method of claim 7, further comprising prior tostep (c): (d) washing the microparticles; and (e) drying themicroparticles.
 10. The method of claim 7, wherein step (c) is carriedout in a temperature-controlled chamber.
 11. The method of claim 7,wherein the conditioning temperature is less than a glass transitiontemperature (T_(g)) of the polymer.
 12. The method of claim 1, whereinthe microparticles comprise a polymer and the conditioning temperatureis less than a glass transition temperature (T_(g)) of the polymer. 13.The method of claim 7, wherein the conditioning temperature is fromabout 20° C. to about 25° C.
 14. The method of claim 7, wherein theactive agent is selected from the group consisting of risperidone,9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof. 15.The method of claim 14, wherein the solvent comprises benzyl alcohol andethyl acetate.
 16. The method of claim 7, wherein the polymer isselected from the group consisting of poly(glycolic acid),poly-d,1-lactic acid, poly-1-lactic acid, and copolymers of theforegoing.
 17. The method of claim 14, wherein the polymer is selectedfrom the group consisting of poly(glycolic acid), poly-d,1-lactic acid,poly-1-lactic acid, and copolymers of the foregoing.
 18. A method forpreparing microparticles having improved flowability, comprising: (a)preparing an emulsion that comprises a first phase and a second phase,wherein the first phase comprises an active agent, a polymer, and asolvent for the polymer; (b) extracting the solvent from the emulsion toform microparticles containing the active agent; (c) introducing themicroparticles into a container; and (d) maintaining the container at aconditioning temperature for a period of time, wherein the conditioningtemperature and the period are selected so that an angle of repose ofthe microparticles is less than about 28°.
 19. The method of claim 18,wherein step (d) comprises: (i) rotating the container. 20.Microparticles having improved flowability prepared by a method,comprising: (a) preparing an emulsion that comprises a first phase and asecond phase, wherein the first phase comprises an active agent, apolymer, and a solvent for the polymer; (b) extracting the solvent fromthe emulsion to form microparticles containing the active agent; and (c)allowing crystal growth of active agent present on a surface of themicroparticles.
 21. The microparticles of claim 20, wherein step (c)comprises: (i) maintaining the microparticles at a conditioningtemperature for a period of time, wherein the conditioning temperatureand the period are selected so that an angle of repose of themicroparticles is less than about 28°.
 22. The microparticles of claim21, wherein the conditioning temperature is less than a glass transitiontemperature (T_(g)) of the polymer.
 23. The method of claim 18, whereinthe conditioning temperature is less than a glass transition temperature(T_(g)) of the polymer.
 24. The microparticles of claim 21, wherein theconditioning temperature is from about 20° C. to about 25° C.
 25. Themicroparticles of claim 20, wherein the active agent is selected fromthe group consisting of risperidone, 9-hydroxyrisperidone, andpharmaceutically acceptable salts thereof.
 26. The microparticles ofclaim 25, wherein the solvent comprises benzyl alcohol and ethylacetate.
 27. The microparticles of claim 20, wherein the polymer isselected from the group consisting of poly(glycolic acid),poly-d,1-lactic acid, poly-1-lactic acid, and copolymers of theforegoing.